Project Summary/Abstract Although more treatment options for advanced prostate cancer (PCa) compared to a decade ago, these therapies are limited to a subset of patients. Thus, it is critical to identify novel therapeutic targets and develop a biomarker-driven approach to stratify patients who will most benefit from targeted therapy, immunotherapy or combination therapy. The career goal of applicant is to leverage cancer genomics and biology to identify therapeutic targets and better combinatory immunotherapies for precision PCa treatment. Applicant recently explored a novel conceptual approach called ?Synthetic Essentiality? to facilitate the identification of essential genes in the context of tumor suppressor gene deficiencies (Zhao et al., Nature 2017). This approach enabled her to identify chromatin-remodeling protein CHD1 as a potential therapeutic target in PTEN-loss PCa, and to uncover mechanistically that CHD1 transcriptionally activates oncogenic NF-?B downstream genes. The overall objective in this application is to search context-specific therapeutic targets as well as combinatorial immunotherapy for PCa harboring deficiencies of the tumor suppressors PTEN, TP53, and RB1, which are enriched in metastasis. Here, the central hypotheses are that CHD1 depletion inhibits the immunosuppressive tumor microenvironment in PCa, and thus inhibiting the CHD1/NF-?B pathway can overcome resistance to immunotherapy; and that the ?Synthetic Essentiality? approach enables identification of therapeutic targets for advanced PCa containing TP53 and RB1 alterations. Guided by strong preliminary data, these hypotheses will be tested by pursuing three Specific Aims: (1) Illuminate the intrinsic and extrinsic mechanisms underlying CHD1 contribution to PCa progression in vivo; (2) Evaluate CHD1/NF-?B inhibition in combination with immune checkpoint blockade; and (3) Identify synthetic essential genes for PCa harboring TP53 or RB1 deficiency. The innovation of this proposal stems from the novel computation-based synthetic essential gene identification approach and newly established PCa mouse models, unbiased analyses using novel technologies of molecular profiling and immunophenotyping, and next-generation whole genome CRISPR screening. The proposed research is significant because it is expected to illuminate precision medicine approaches for patients with advanced PCa containing diverse cancer genomics, and establish an operable pipeline to explore targeted therapeutics for broad cancer types. It will also position the applicant to submit a competitive R01 application during the 4th year of the proposed Award. In addition, applicant has assembled an extraordinary co-mentor team consisting of Drs. Ronald DePinho, James Allison and Christopher J. Logothetis, who will expand her training in PCa mouse modeling, cancer immunology, immunotherapy and prostate cancer translational research, and will support her transition to independence. In addition, the outstanding intellectual environment, technical resources, and facilities at MD Anderson Cancer Center will enable the applicant to achieve her proposed project goals and develop her independent career in the award period.